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1: Cancer Is a Group of Diseases Characterized by Cell Proliferation
Estimated incidences of various
cancers and cancer mortality
in the United States in 2009
Lung and bronchus
Colon and rectum
Oral cavity and pharynx
Brain and nervous system
Cancers of soft
tissues including heart
Type of Cancer
Source: American Cancer Society, Cancer Facts and Figures, 2009
(Atlanta: American Cancer Society, 2009), p. 4.
separate from the tumor and travel to distant sites in the
body, where they may take up residence and develop into
new tumors. The most common cancers in the United States
are those of the breast, prostate, lung, colon and rectum, and
blood (Table 15.1).
Normal cells grow, divide, mature, and die in response to
a complex set of internal and external signals. A normal
cell receives both stimulatory and inhibitory signals, and
its growth and division are regulated by a delicate balance
between these opposing forces. In a cancer cell, one or
more of the signals has been disrupted, which causes the
cell to proliferate at an abnormally high rate. As they lose
their response to the normal controls, cancer cells gradually lose their regular shape and boundaries, eventually
forming a distinct mass of abnormal cells—a tumor. If the
cells of the tumor remain localized, the tumor is said to be
benign; if the cells invade other tissues, the tumor is said
to be malignant. Cells that travel to other sites in the body,
where they establish secondary tumors, have undergone
Cancer As a Genetic Disease
Cancer arises as a result of fundamental defects in the regulation of cell division, and its study therefore has significance not only for public health, but also for our basic
understanding of cell biology. Through the years, a large
number of theories have been put forth to explain cancer,
but we now recognize that most, if not all, cancers arise
from defects in DNA.
Early observations suggested that cancer might result
from genetic damage. First, many agents, such as ionizing
radiation and chemicals that cause mutations also cause cancer (are carcinogens). Second, some cancers are consistently
associated with particular chromosome abnormalities.
About 90% of people with chronic myeloid leukemia, for
example, have a reciprocal translocation between chromosome 22 and chromosome 9. Third, some specific types of
cancers tend to run in families. Retinoblastoma, a rare childhood cancer of the retina, appears with high frequency in a
few families and is inherited as an autosomal dominant trait,
suggesting that a single gene is responsible for these cases of
Although these observations hinted that genes play
some role in cancer, the theory of cancer as a genetic disease
had several significant problems. If cancer is inherited, every
cell in the body should receive the cancer-causing gene, and
therefore every cell should become cancerous. In those types
of cancer that run in families, however, tumors typically
appear only in certain tissues and often only when the person reaches an advanced age. Finally, many cancers do not
run in families at all and, even in regard to those cancers that
generally do, isolated cases crop up in families with no history of the disease.
Knudson’s multistep model of cancer In 1971, Alfred
Knudson proposed a model to explain the genetic basis of
cancer. Knudson was studying retinoblastoma, a cancer
that usually develops in only one eye but occasionally
appears in both. Knudson found that, when retinoblastoma
appears in both eyes, it presents itself at an early age and
many affected children have close relatives who also are
Knudson proposed that retinoblastoma results from
two separate genetic defects, both of which are necessary for
cancer to develop (Figure 15.3). He suggested that, in the
cases in which the disease affects just one eye, a single cell in
one eye undergoes two successive mutations. Because the
chance of these two mutations occurring in a single cell is
remote, retinoblastoma is rare and typically develops in only
one eye. For the bilateral case, Knudson proposed that the
1 Rarely, a single cell
2 …resulting in a single
tumor, for example,
in one eye.
4 Some cells undergo a
single somatic mutation
that produces cancer.
3 A predisposed
5 Because only a single mutation is required to
produce cancer, the likelihood of its occurring
twice (in both eyes, for example) increases.
Conclusion: Multiple mutations are
required to produce cancerous cells.
15.3 Alfred Knudson proposed that retinoblastoma results from two separate genetic
defects, both of which are necessary for cancer to develop.
child inherited one of the two mutations required for the
cancer, and so every cell contains this initial mutation. In
these cases, all that is required for cancer to develop is for one
eye cell to undergo the second mutation. Because each eye
possesses millions of cells, the probability that the second
mutation will occur in at least one cell of each eye is high,
producing tumors in both eyes at an early age.
Knudson’s proposal suggests that cancer is the result of
a multistep process that requires several mutations. If one or
more of the required mutations is inherited, fewer additional mutations are required to produce cancer, and the
cancer will tend to run in families. The idea that cancer
results from multiple mutations turns out to be correct for
Knudson’s genetic theory for cancer has been confirmed
by the identification of genes that, when mutated, cause cancer. Today, we recognize that cancer is fundamentally a
genetic disease, although few cancers are actually inherited.
Most tumors arise from somatic mutations that accumulate
in a person’s life span, either through spontaneous mutation
or in response to environmental mutagens.
The clonal evolution of tumors Cancer begins when a
single cell undergoes a mutation that causes the cell to divide
at an abnormally rapid rate. The cell proliferates, giving rise
to a clone of cells, each of which carries the same mutation.
Because the cells of the clone divide more rapidly than normal, they soon outgrow other cells. An additional mutation
that arises in some of the clone’s cells may further enhance
the ability of those cells to proliferate, and cells carrying both
mutations soon become dominant in the clone. Eventually,
they may be overtaken by cells that contain yet more mutations that enhance proliferation. In this process, called clonal
evolution, the tumor cells acquire more mutations that allow
them to become increasingly more aggressive in their proliferative properties (Figure 15.4).
The rate of clonal evolution depends on the frequency
with which new mutations arise. Any genetic defect that
1 A cell is predisposed
to proliferate at an
abnormally high rate.
Mutations in genes that affect chromosome segregation also may contribute to the clonal evolution of tumors.
Many cancer cells are aneuploid, and it is clear that chromosome mutations contribute to cancer progression by
duplicating some genes (those on extra chromosomes) and
eliminating others (those on deleted chromosomes).
Cellular defects that interfere with chromosome separation
increase aneuploidy and may therefore accelerate cancer
2 A second mutation
causes the cell to
3 After a third mutation, the cell
undergoes structural changes.
Cancer is fundamentally a genetic disease. Mutations in several
genes are usually required to produce cancer. If one of these mutations is inherited, fewer somatic mutations are necessary for cancer to develop, and the person may have a predisposition to
cancer. Clonal evolution is the accumulation of mutations in a
clone of cells.
✔ Concept Check 1
How does the multistep model of cancer explain the observation
that sporadic cases of retinoblastoma usually appear in only one eye,
whereas inherited forms of the cancer appear in both eyes?
4 A fourth mutation causes the cell to divide
uncontrollably and invade other tissues.
15.4 Through clonal evolution, tumor cells acquire multiple
mutations that allow them to become increasingly
aggressive and proliferative. To conserve space, a dashed arrow is
used to represent a second cell of the same type in each case.
allows more mutations to arise will accelerate cancer progression. Genes that regulate DNA repair are often found to
have been mutated in the cells of advanced cancers, and
inherited disorders of DNA repair are usually characterized
by increased incidences of cancer. Because DNA-repair
mechanisms normally eliminate many of the mutations that
arise, cells with defective DNA-repair systems are more likely
to retain mutations than are normal cells, including mutations in genes that regulate cell division. Xeroderma
pigmentosum, for example, is a rare disorder caused by a
defect in DNA repair (see the introduction to Chapter 9 and
pp. 341–342 in Chapter 13). People with this condition have
elevated rates of skin cancer when exposed to sunlight
(which induces mutation).
The Role of Environmental
Factors in Cancer
Although cancer is fundamentally a genetic disease, most
cancers are not inherited, and there is little doubt that
many cancers are influenced by environmental factors. The
role of environmental factors in cancer is suggested by differences in the incidence of specific cancers throughout the
world (Table 15.2). The results of studies show that
migrant populations typically take on the cancer incidence
of their host country. For example, the overall rates of cancer are considerably lower in Japan than in Hawaii.
However, within a single generation after migration to
Hawaii, Japanese people develop cancer at rates similar to
those of native Hawaiians.
Smoking is a good example of an environmental factor
that is strongly associated with cancer. Other environmental
factors that induce cancer are certain types of chemicals,
such as benzene (used as an industrial solvent),
benzo[a]pyrene (found in cigarette smoke), and polychlorinated biphenyls (PCBs; used in industrial transformers and
capacitors). Ultraviolet light, ionizing radiation, and viruses
are other known carcinogens and are associated with variation in the incidence of many cancers. Most environmental
factors associated with cancer cause somatic mutations that
stimulate cell division or otherwise affect the process of cancer progression.
Examples of geographic
variation in the incidence
United States (Utah)
United States (Iowa)
United States (New
Orleans, African Americans)
United States (Utah)
Source: C. Muir et al., Cancer Incidence in Five Continents, vol. 5 (Lyon:
International Agency for Research on Cancer, 1987), Table 12-2.
*The incidence rate is the age-standardized rate in males per 100,000
15.2 Mutations in a Number
of Different Types of Genes
Contribute to Cancer
As we have seen, cancer is a disease caused by alterations in
the DNA. There are, however, many different types of genetic
alterations that may contribute to cancer. In the next several
sections, we will outline some of the different types of genes
that frequently have roles in cancer.
Oncogenes and Tumor-Suppressor
The signals that regulate cell division fall into two basic
types: molecules that stimulate cell division and those that
inhibit it. These control mechanisms are similar to the accelerator and brake of an automobile. In normal cells (but, one
would hope, not your car), both accelerators and brakes are
applied at the same time, causing cell division to proceed at
the proper speed.
Because cell division is affected by both accelerators and
brakes, cancer can arise from mutations in either type of signal, and there are several fundamentally different routes to
cancer (Figure 15.5). A stimulatory gene can be made hyperactive or active at inappropriate times, analogous to having
the accelerator of an automobile stuck in the floored position. Mutations in stimulatory genes are usually dominant
because a mutation in a single copy of the gene is usually sufficient to produce a stimulatory effect. Dominant-acting
stimulatory genes that cause cancer are termed oncogenes.
Cell division may also be stimulated when inhibitory genes
are made inactive, analogously to having a defective brake in
an automobile. Mutated inhibitory genes generally have
recessive effects because both copies must be mutated to
remove all inhibition. Inhibitory genes in cancer are termed
tumor-suppressor genes. Many cancer cells have mutations
in both oncogenes and tumor-suppressor genes.
Although oncogenes or mutated tumor-suppressor
genes or both are required to produce cancer, mutations in
DNA-repair genes can increase the likelihood of acquiring
mutations in these genes. Having mutated DNA-repair genes
is analogous to having a lousy car mechanic who does not
make the necessary repairs on a broken accelerator or brake.
Oncogenes Oncogenes were the first cancer-causing genes
to be identified. In 1909, a farmer brought physician Peyton
Rous a hen with a large connective-tissue tumor (sarcoma)
growing on its breast. When Rous injected pieces of this
tumor into other hens, they also developed sarcomas. Rous
conducted experiments that demonstrated that the tumors
were being transmitted by a virus, which became known as
the Rous sarcoma virus, as mentioned in Chapter 6. A number of other cancer-causing viruses were subsequently isolated from various animal tissues. These viruses were
generally assumed to carry a cancer-causing gene that was
transferred to the host cell. The first oncogene, called src, was
isolated from the Rous sarcoma virus in 1970.
In 1975, Michael Bishop, Harold Varmus, and their colleagues began to use probes for viral oncogenes to search for
related sequences in normal cells. They discovered that the
genomes of all normal cells carry DNA sequences that are
closely related to viral oncogenes. These cellular genes are
called proto-oncogenes. They are responsible for basic cellular functions in normal cells but, when mutated, they
become oncogenes that contribute to the development of
cancer. When a virus infects a cell, a proto-oncogene may
become incorporated into the viral genome through recombination. Within the viral genome, the proto-oncogene may
mutate to an oncogene that, when inserted back into a cell,
causes rapid cell division and cancer. Because the protooncogenes are more likely to undergo mutation or recombination within a virus, viral infection is often associated with
(b) Tumor-suppressor genes
wild type (+/+)
factors that stimulate
2 Mutant alleles (oncogenes) tend
to be dominant: one copy of the
mutant allele is sufficient to
induce excessive cell proliferation.
wild type (+/+)
(or mutation in one
and deletion in one)
Normal growthNo inhibitory No inhibitory
produce factors that
inhibit cell division.
4 Mutant alleles are recessive
(both alleles must be
mutated to produce excessive
15.5 Both oncogenes (a) and tumor-suppressor genes (b) contribute to cancer but differ in
their modes of action and dominance.
Proto-oncogenes can be converted into oncogenes in
viruses by several different ways. The sequence of the protooncogene may be altered or truncated as it is being incorporated into the viral genome. This mutated copy of the gene
may then produce an altered protein that causes uncontrolled cell proliferation. Alternatively, through recombination, a proto-oncogene may end up next to a viral promoter
or enhancer, which then causes the gene to be overexpressed.
Finally, sometimes the function of a proto-oncogene in the
Some oncogenes and functions
of their corresponding
Part of growth-factor
Protein tyrosine kinase
GTP binding and GTPase
host cell may be altered when a virus inserts its own DNA
into the gene, disrupting its normal function.
Many oncogenes have been identified by experiments in
which selected fragments of DNA are added to cells in culture. Some of the cells take up the DNA and, if these cells
become cancerous, then the DNA fragment that was added
to the culture must contain an oncogene. The fragments can
then be sequenced, and the oncogene can be identified. A
large number of oncogenes have now been discovered
Tumor-suppressor genes Tumor-suppressor genes are
more difficult than oncogenes to identify because they
inhibit cancer and are recessive; both alleles must be mutated
before the inhibition of cell division is removed. Because it is
the failure of their function that promotes cell proliferation,
tumor-suppressor genes cannot be identified by adding
them to cells and looking for cancer. Defects in both copies
of a tumor-suppressor gene are usually required to cause
cancer; an organism can inherit one defective copy of the
tumor-suppressor gene (is heterozygous for the cancer-causing mutation) and not have cancer, because the remaining
normal allele produces the tumor-suppressing product.
However, these heterozygotes are often predisposed to cancer, because inactivation or loss of the one remaining allele
is all that is required to completely eliminate the tumor-suppressor product and is referred to as loss of heterozygosity.
A common mechanism for loss of heterozygosity is a deletion on the chromosome that carried the normal copy of the
tumor-suppressor gene (Figure 15.6).
One of the first tumor-suppressor genes to be identified
was the retinoblastoma gene. In 1985, Raymond White and